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Journal of Virology, November 2003, p. 12276-12284, Vol. 77, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.22.12276-12284.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Latent Membrane Protein 2A Activates ß-Catenin Signaling in Epithelial Cells

J. A. Morrison,1 A. J. Klingelhutz,2 and N. Raab-Traub1,3*

Department of Microbiology and Immunology,1 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599,3 Department of Microbiology, University of Iowa, Iowa City, Iowa 522422

Received 23 May 2003/ Accepted 15 August 2003

The Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) functions to maintain latency in EBV-infected B lymphocytes. Although LMP2A is nonessential for the immortalization of B lymphocytes by EBV, its expression in B lymphocytes prevents viral reactivation by blocking B-cell receptor activation and signaling. LMP2A also provides an antiapoptotic signal in transgenic mice that express LMP2A in B lymphocytes. LMP2A activates phosphatidylinositol 3-kinase (PI3K) and the serine/threonine kinase Akt in lymphocytes and epithelial cells. Here we show that EBV LMP2A activates the PI3K and ß-catenin signaling pathways in telomerase-immortalized human foreskin keratinocytes (HFK). LMP2A activated Akt in a PI3K-dependent manner, and the downstream Akt targets glycogen synthase kinase 3ß (GSK3ß) and the Forkhead transcription factor FKHR were phosphorylated and inactivated in LMP2A-expressing HFK cells. GSK3ß is a negative regulator of the Wnt signaling pathway, and inactivation of GSK3ß by LMP2A signaling led to stabilization of ß-catenin, the central oncoprotein of Wnt signaling. In LMP2A-expressing cells, ß-catenin accumulated in the cytoplasm and translocated into the nucleus via a two-step mechanism. The cytoplasmic accumulation of ß-catenin downstream of LMP2A was independent of PI3K signaling, whereas its nuclear translocation was dependent on PI3K signaling. In the nucleus, ß-catenin activated a reporter responsive to T-cell factor, and this activation was augmented by LMP2A coexpression. The Wnt pathway is inappropriately activated in 90% of colon cancers and is dysregulated in several other cancers, and these data suggest that activation of this pathway by LMP2A may contribute to the generation of EBV-associated cancers.

* Corresponding author. Mailing address: Lineberger Cancer Center, University of North Carolina-Chapel Hill, Mason Farm Rd., Rm. 102, Chapel Hill, NC 27599. Phone: (919) 966-1701. Fax: (919) 966-9673. E-mail: nrt{at}med.unc.edu.

Journal of Virology, November 2003, p. 12276-12284, Vol. 77, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.22.12276-12284.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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